Substance P (SP) is contained in small dorsal root ganglia, is transported peripherally, and is present in peripheral nerve terminals in knee joint and skin. The comparable actions of local SP and the antidromic stimulation of somatic afferents suggest that these peripheral stores of SP may be releasable, a likelihood specifically supported by a currently modest literature. In the proposed studies, all performed in terminally anesthetized cats, perfusates of the synovial space of the knee joint (KJ) and the intradermal space of a skin bleb or the spontaneous outflow of the saphenous lymph duct will be assayed for SP-LI. We will address four specific hypothesis: 1) "SP-like immunoreactivity (SP-LI) is released in a Ca++ dependent fashion into the interstitial space from the peripheral nerve terminals of small, unmyelinated sensory afferents". Specifically, we will examine the SP-LI secretion evoked by antidromic stimulation of the sciatic nerve, with regard to effective stimulus intensity, frequency dependency, apparent relative refractory period; Ca++ dependency and the local releasing and desensitizing effects of capsaicin. 2) "SP-LI release from the peripheral terminal occurs as a function of local thermal and chemical stimulation". Specifically, the effects of 35 degrees C and 60 degrees C stimuli; and the dose dependent effects of locally applied bradykinin, histamine, prostaglandins E2 and capsaicin will be examined. A corollary to this hypothesis is that manipulations which result in sensitization of the peripheral terminal of the afferent will facilitate the peripheral release of SP-LI. This will be examined in the KJ using an acute inflammatory response evoked by intrasynovial injection of kaolin and carrageenan. 3) "The antidromic evoked release of peripheral SP-LI is subject to modulation by several classes of local receptors, including those for mu, delta, kappa opioid, alpha 1 and alpha 2 adrenergic agonists, adenosine, GABA, and somatostatin". 4) "Pharmacological agents which modulate the peripheral secretion of SP-LI will predictably alter a physiologic effect produced by antidromic activation of the somatic afferents, notably an increase in capillary permeability". These studies will thus describe the pharmacology and physiology of the peripheral terminals of primary afferents which secrete SP-LI. Current evidence clearly suggests that such antidromic release may play a prominent role not only in local inflammatory reactions, but in a variety of important pathological states including arthritis.